Cohort Profile: The Precipitating Events Project (PEP Study).

The Precipitating Events Project (PEP Study) is an ongoing longitudinal study of 754 nondisabled community-living persons age 70 years or older who were members of a large health plan in greater New Haven, Connecticut, USA. The study was established to rigorously evaluate the epidemiology of disability in older persons and to elucidate the role of intervening illnesses and injuries on the disabling process. Of the eligible members, 75.2% agreed to participate and were enrolled between March 1998 and October 1999. Participants have completed comprehensive home-based assessments at 18-month intervals and have been interviewed monthly over the phone with a completion rate of 99%. Detailed participant-level data on health care utilization are obtained annually through linkages with Medicare claims. Through June 2019, 702 (93.1%) participants have died after a median of 109 months, while 43 (5.7%) have dropped out of the study after a median of 27 months. Death certificates are available for all decedents. To date, 117 original reports have been published using data from the PEP Study, including many focusing on other high priority areas such as end of life, frailty, depressive symptoms, aging stereotypes, pain, sleep, and methodologic research. The PEP Study welcomes proposals to access data for meritorious analyses from qualified investigators.

Editor's Choice - Inequalities in Abdominal Aortic Aneurysm Screening in England: Effects of Social Deprivation and Ethnicity.

OBJECTIVE: Population screening for abdominal aortic aneurysm (AAA) in men is currently ongoing in several countries. The aim was to examine the effects of deprivation and ethnicity on uptake of screening for abdominal aortic aneurysm (AAA) and prevalence of AAA. METHODS: This was a review of outcomes from a population screening programme using data collected contemporaneously on a bespoke national database. Men aged 65 in two annual cohorts (2013/14 and 2014/15) were invited for AAA screening. Attendance and prevalence of AAA (aortic diameter >2.9 cm) were recorded. Results were compared according to measures of social deprivation and recorded ethnicity. RESULTS: Some 593,032 men were invited and 461,898 attended for ultrasound screening; uptake 77.9%. Uptake was related to social deprivation: 65.1% in the most deprived decile, 84.1% in the least deprived: OR for least deprived 2.84, 95% CI 2.76-2.92, p<.0001. Men in deprived areas were more likely to actively decline screening: 6% versus 3.8% in the least deprived decile. AAA were twice as common in the most deprived compared with the least deprived decile: OR 2.1, 95% CI 1.77-2.27, p<.0001. AAA were more common in white British men than in black (OR 0.46, 95% CI 0.31-0.71) or Asian (OR 0.18, 95% CI 0.13-0.26) men. There was considerable local variation in all findings. CONCLUSIONS: Social deprivation affects uptake of AAA screening in 65 year old men. Local factors are the most important determinants of uptake, so solutions to improve uptake must be designed at local, not national level.

Diagnostic accuracy of DXA compared to conventional spine radiographs for the detection of vertebral fractures in children.

OBJECTIVES: In children, radiography is performed to diagnose vertebral fractures and dual energy x-ray absorptiometry (DXA) to assess bone density. In adults, DXA assesses both. We aimed to establish whether DXA can replace spine radiographs in assessment of paediatric vertebral fractures. METHODS: Prospectively, lateral spine radiographs and lateral spine DXA of 250 children performed on the same day were independently scored by three radiologists using the simplified algorithm-based qualitative technique and blinded to results of the other modality. Consensus radiograph read and second read of 100 random images were performed. Diagnostic accuracy, inter/intraobserver and intermodality agreements, patient/carer experience and radiation dose were assessed. RESULTS: Average sensitivity and specificity (95 % confidence interval) in diagnosing one or more vertebral fractures requiring treatment was 70 % (58-82 %) and 97 % (94-100 %) respectively for DXA and 74 % (55-93 %) and 96 % (95-98 %) for radiographs. Fleiss' kappa for interobserver and average kappa for intraobserver reliability were 0.371 and 0.631 respectively for DXA and 0.418 and 0.621 for radiographs. Average effective dose was 41.9 µSv for DXA and 232.7 µSv for radiographs. Image quality was similar. CONCLUSION: Given comparable image quality and non-inferior diagnostic accuracy, lateral spine DXA should replace conventional radiographs for assessment of vertebral fractures in children. KEY POINTS: • Vertebral fracture diagnostic accuracy of lateral spine DXA is non-inferior to radiographs. • The rate of unreadable vertebrae for DXA is lower than for radiographs. • Effective dose of DXA is significantly lower than radiographs. • Children prefer DXA to radiographs. • Given the above, DXA should replace radiographs for paediatric vertebral fracture assessment.

Impact of the first 5 years of a national abdominal aortic aneurysm screening programme.

BACKGROUND: The Abdominal Aortic Aneurysm (AAA) Screening Programme was introduced by the National Health Service (NHS) in England to reduce the rate of death from ruptured AAA in men. The programme commenced in 2009 and was implemented completely across the country in April 2013. The aim was to review the first 5 years of the programme, looking specifically at compliance and early outcome. METHODS: Men aged 65 years were invited for a single abdominal ultrasound scan. Data were entered into a bespoke database (AAA SMaRT). This was a planned analysis after the first 5 years of the programme. RESULTS: The summation analysis involved the first 700 000 men screened, and the first 1000 men with a large AAA referred for possible treatment. The prevalence of AAA (aortic diameter larger than 2·9 cm) in 65-year-old men was 1·34 per cent. Mean uptake was 78·1 per cent, but varied from 61·7 to 85·8 per cent across the country. Based on the Index of Multiple Deprivation, uptake was 65·1 per cent in the most deprived versus 84·1 per cent in the least deprived areas. Of the first 1000 men referred for possible treatment of a large AAA (greater than 5·4 cm), the false-positive rate was 3·2 per cent. Some 870 men underwent a planned AAA intervention (non-intervention rate 9·2 per cent), with seven deaths (perioperative mortality rate 0·8 per cent). CONCLUSION: The processes in the NHS AAA Screening Programme are effective in detecting and treating men with AAA.

Diagnosis of vertebral fractures in children: is a simplified algorithm-based qualitative technique reliable?

BACKGROUND: Identification of osteoporotic vertebral fractures allows treatment opportunity reducing future risk. There is no agreed standardised method for diagnosing paediatric vertebral fractures. OBJECTIVE: To evaluate the precision of a modified adult algorithm-based qualitative (ABQ) technique, applicable to children with primary or secondary osteoporosis. MATERIALS AND METHODS: Three radiologists independently assessed lateral spine radiographs of 50 children with suspected reduction in bone mineral density using a modified ABQ scoring system and following simplification to include only clinically relevant parameters, a simplified ABQ score. A final consensus of all observers using simplified ABQ was performed as a reference standard for fracture characterisation. Kappa was calculated for interobserver agreement of the components of both scoring systems and intraobserver agreement of simplified ABQ based on a second read of 29 randomly selected images. RESULTS: Interobserver Kappa for modified ABQ scoring for fracture detection, severity and shape ranged from 0.34 to 0.49 Kappa for abnormal endplate and position assessment was 0.27 to 0.38. Inter- and intraobserver Kappa for simplified ABQ scoring for fracture detection and grade ranged from 0.37 to 0.46 and 0.45 to 0.56, respectively. Inter- and intraobserver Kappa for affected endplate ranged from 0.31 to 0.41 and 0.45 to 0.51, respectively. Subjectively, observers' felt simplified ABQ was easier and less time-consuming. CONCLUSION: Observer reliability of modified and simplified ABQ was similar, with slight to moderate agreement for fracture detection and grade/severity. Due to subjective preference for simplified ABQ, we suggest its use as a semi-objective measure of diagnosing paediatric vertebral fractures.

Metabolic outcomes 2 years following gastric bypass surgery in people with type 2 diabetes: an observational cohort study.

BACKGROUND: Gastric bypass surgery induces early remission or significant improvement in type 2 diabetes (T2D). AIM: To assess effectiveness of stopping glucose-lowering treatment at the time of surgery. DESIGN: Observational cohort analysis. METHODS: We identified 101 patients (62 women) with T2D who had undergone gastric bypass surgery at a mean (SD, standard deviation) age of 51.4 (9.0) years. We recorded weight, body mass index (BMI), glycosylated haemoglobin (HbA1c), blood pressure (BP), total and high-density lipoprotein (HDL) cholesterol preoperatively and at a median 4, 12 and 24 months postoperatively, and changes to glucose-lowering therapy. RESULTS: Mean (SD) baseline BMI was 50.3 (6.3) kg/m(2), HbA1c 65.3 (18.5) mmol/mol, systolic BP 146.0 (18.0) mmHg, diastolic BP 87.0 (10.8) mmHg and total cholesterol-to-HDL cholesterol ratio 4.0 (1.2). Mean (95% confidence interval) reduction in BMI was 16.4 (14.1-18.7) kg/m(2), HbA1c 23.6 (17.6-29.6) mmol/mol, systolic BP 12.9 (5.9-19.8) mmHg, diastolic BP 6.1 (1.8-10.5) mmHg and total cholesterol-to-HDL cholesterol ratio 1.1 (0.6-1.5) at 24 months (P < 0.001 for all measures). Although 91% of patients were receiving glucose-lowering therapies preoperatively, complete (HbA1c < 42 mmol/mol) and partial (HbA1c 42-48 mmol/mol) remissions of T2D were seen in 62.1% and 5.2% at 2 years postoperatively. CONCLUSIONS: Cessation of glucose-lowering therapies in people with T2D at the time of gastric bypass surgery was clinically effective. The majority of patients remained in complete or partial remission of diabetes up to 2 years postoperatively.

The effectiveness and cost of single and multi-factorial cardiovascular risk factor modification to guideline targets in type 2 diabetes.

AIMS: Cardiovascular disease is the main cause of morbidity and mortality in type 2 diabetes (T2DM), at huge cost to the NHS. We investigated the potential effect on population cardiovascular risk and associated costs of single and multi-factorial intervention, to target levels, in individuals with T2DM. METHODS: Baseline population means and proportions for cardiovascular risk factors were calculated for 159 patients with T2DM from 3 general practices. Predicted 10year cardiovascular risk, and associated costs were calculated using the LIP2687 risk calculator, based on Framingham and UKPDS equations. Systolic blood pressure, HbA(1C), total cholesterol and HDL-cholesterol were altered to NICE and SIGN target levels and the model run again. The difference in outcomes was observed. RESULTS: 45%, 76% and 38% of patients met NICE targets for cholesterol, systolic blood pressure and HbA1c, respectively. As expected, comparing the two guidelines, fewer patients met the 'stricter' targets (P=0.0001). Treatment-to-target produced no significant difference in cardiovascular risk or costs, although greater reductions in outcomes were seen with multi-factorial intervention. CONCLUSION: This small study suggests that intervention in only those patients with the highest cardiovascular risk brings little reduction in population cardiovascular risk and associated health costs. Multi-factorial intervention in all patients with T2DM, regardless of baseline values, is likely to bring greater reductions. This raises the question as to whether the current emphasis on treatment to target should be modified to encourage multi-factorial intervention in all patients with T2DM, even those with baseline values below target levels.

Bayesian hierarchical modeling for a non-randomized, longitudinal fall prevention trial with spatially correlated observations.

Because randomization of participants is often not feasible in community-based health interventions, non-randomized designs are commonly employed. Non-randomized designs may have experimental units that are spatial in nature, such as zip codes that are characterized by aggregate statistics from sources like the U.S. census and the Centers for Medicare and Medicaid Services. A perennial concern with non-randomized designs is that even after careful balancing of influential covariates, bias may arise from unmeasured factors. In addition to facilitating the analysis of interventional designs based on spatial units, Bayesian hierarchical modeling can quantify unmeasured variability with spatially correlated residual terms. Graphical analysis of these spatial residuals demonstrates whether variability from unmeasured covariates is likely to bias the estimates of interventional effect. The Connecticut Collaboration for Fall Prevention is the first large-scale longitudinal trial of a community-wide healthcare intervention designed to prevent injurious falls in older adults. Over a two-year evaluation phase, this trial demonstrated a rate of fall-related utilization at hospitals and emergency departments by persons 70 years and older in the intervention area that was 11 per cent less than that of the usual care area, and a 9 per cent lower rate of utilization from serious injuries. We describe the Bayesian hierarchical analysis of this non-randomized intervention with emphasis on its spatial and longitudinal characteristics. We also compare several models, using posterior predictive simulations and maps of spatial residuals.

Trends in the association between blood pressure and obesity in a Taiwanese population between 1996 and 2006.

In the last decades, the prevalence of obesity has increased in the Taiwanese population. This has the potential to impact on the risks of cardiovascular diseases and diabetes. This study investigated trends in the changes in several indices of obesity in the last decade, and the relationship between blood pressure (BP) and these obesity indices available in Mei-Jaw Corporation health-screening data from 1996/1998 to 2006. Three cross-sectional surveys among healthy individuals ages 20-59 years, in which 14,362 subjects examined in year 1996, 17,368 in 1998, and 28,524 in 2006, were included in the analysis. Body weight and height data were available from 1996, whereas %body fat, waist circumference and waist-hip ratio (Whratio) were only available from 1998 onwards. We found that the association between systolic BP and body weight, body mass index, %body fat, Whratio and waist became stronger for both men and women in 2006 than 1996 after adjustment for age, education level, alcohol intake, smoking and betel nut chewing. In contrast, non-obese people seemed to have lower diastolic BP in 2006 than in 1996. This trend is consistent irrespective of the index of obesity used. Among healthy individuals, the average values for the obesity indices increased in men but remained similar in women. However, in both men and women, the relationship between obesity and BP has changed. Further research is required to investigate the impact of these intriguing changes in the associations on the risk of cardiovascular diseases in the Taiwanese population.

Resolvin D1 controls inflammation initiated by glutathione-lipid conjugates formed during oxidative stress.

BACKGROUND AND PURPOSE: Inflammation is associated with oxidative stress and local generation of lipid peroxidation-derived aldehydes, such as 4-hydroxy-trans-2-nonenal (HNE). In most tissues, HNE is readily conjugated with glutathione and presently it is unknown whether glutathionyl-HNE (GS-HNE) plays a functional role in inflammation. Here, we sought to determine whether GS-HNE is a mediator of oxidative stress-initiated inflammation and if its actions can be regulated by the anti-inflammatory and pro-resolving lipid mediator, resolvin D1 (RvD1). EXPERIMENTAL APPROACH: GS-HNE was administered intraperitoneally to mice and peritoneal lavages were assessed for leukocyte infiltration and lipid mediators were targeted by mediator-lipidomics. RvD1 was administered to mice treated with GS-HNE and leukocyte infiltration was assessed in the peritoneum. Superoxide production and CD11b modulation were measured in isolated human polymorphonuclear leukocytes incubated with GS-HNE. KEY RESULTS: GS-HNE (1-10 microg) evoked infiltration of Gr-1(+) leukocytes into the peritoneum to form an inflammatory exudate. With isolated human polymorphonuclear leukocytes, GS-HNE stimulated both superoxide generation and CD11b expression. Among the lipid mediators, both cyclooxygenase- and lipoxygenase-derived pro-inflammatory eicosanoids, including prostaglandin E(2), leukotriene B(4) and cysteinyl leukotrienes, were generated in exudates of mice injected intraperitoneally with GS-HNE. RvD1, given i.v. in doses as low as 0.01-10.0 ng, sharply reduced GS-HNE-stimulated leukocyte infiltration ( approximately 30-70%). CONCLUSIONS AND IMPLICATIONS: Glutathione conjugates of HNE, derived during oxidative stress, are pro-inflammatory in vivo. RvD1 protects against this oxidative stress-initiated inflammation.

Contribution of nonneutralizing vaccine-elicited antibody activities to improved protective efficacy in rhesus macaques immunized with Tat/Env compared with multigenic vaccines.

Previously, chronic-phase protection against SHIV(89.6P) challenge was significantly greater in macaques primed with replicating adenovirus type 5 host range mutant (Ad5hr) recombinants encoding HIVtat and env and boosted with Tat and Env protein compared with macaques primed with multigenic adenovirus recombinants (HIVtat, HIVenv, SIVgag, SIVnef) and boosted with Tat, Env, and Nef proteins. The greater protection was correlated with Tat- and Env-binding Abs. Because the macaques lacked SHIV(89.6P)-neutralizing activity prechallenge, we investigated whether Ab-dependent cellular cytotoxicity (ADCC) and Ab-dependent cell-mediated viral inhibition (ADCVI) might exert a protective effect. We clearly show that Tat can serve as an ADCC target, although the Tat-specific activity elicited did not correlate with better protection. However, Env-specific ADCC activity was consistently higher in the Tat/Env group, with sustained cell killing postchallenge exhibited at higher levels (p < 0.00001) for a longer duration (p = 0.0002) compared with the multigenic group. ADCVI was similarly higher in the Tat/Env group and significantly correlated with reduced acute-phase viremia at wk 2 and 4 postchallenge (p = 0.046 and 0.011, respectively). Viral-specific IgG and IgA Abs in mucosal secretions were elicited but did not influence the outcome of the i.v. SHIV(89.6P) challenge. The higher ADCC and ADCVI activities seen in the Tat/Env group provide a plausible mechanism responsible for the greater chronic-phase protection. Because Tat is known to enhance cell-mediated immunity to coadministered Ags, further studies should explore its impact on Ab induction so that it may be optimally incorporated into HIV vaccine regimens.

Correlation of vaccine-elicited systemic and mucosal nonneutralizing antibody activities with reduced acute viremia following intrarectal simian immunodeficiency virus SIVmac251 challenge of rhesus macaques.

Cell-mediated immunity and neutralizing antibodies contribute to control of human immunodeficiency virus/simian immunodeficiency virus (HIV/SIV) infection, but the role of nonneutralizing antibodies is not defined. Previously, we reported that sequential oral/oral or intranasal/oral (I/O) priming with replication-competent adenovirus type 5 host range mutant (Ad5hr)-SIV recombinants, followed by intramuscular envelope protein boosting, elicited systemic and mucosal cellular immunity and exhibited equivalent, significant reductions of chronic viremia after rectal SIV(mac251) challenge. However, I/O priming gave significantly better control of acute viremia. Here, systemic and mucosal humoral immunity were investigated for potential correlates with the acute challenge outcome. Strong serum binding but nonneutralizing antibody responses against SIV(mac251) were induced in both groups. Antibody responses appeared earlier and overall were higher in the I/O group. Reduced acute viremia was significantly correlated with higher serum binding titer, stronger antibody-dependent cellular cytotoxicity activity, and peak prechallenge and 2-week-postchallenge antibody-dependent cell-mediated viral inhibition (ADCVI). The I/O group consistently displayed greater anti-envelope immunoglobulin A (IgA) antibody responses in bronchoalveolar lavage and a stronger rectal anti-envelope IgA anamnestic response 2 weeks postchallenge. Pre- and postchallenge rectal secretions inhibited SIV transcytosis across epithelial cells. The inhibition was significantly higher in the I/O group, although a significant correlation with reduced acute viremia was not reached. Overall, the replicating Ad5hr-SIV priming/envelope boosting approach elicited strong systemic and mucosal antibodies with multiple functional activities. The pattern of elevated immune responses in the I/O group is consistent with its better control of acute viremia mediated, at least in part, by ADCVI activity and transcytosis inhibition.

Comparison of techniques for decompressive lumbar laminectomy: the minimally invasive versus the "classic" open approach.

OBJECT: Decompressive laminectomy offers an effective surgical treatment of lumbar spinal stenosis. The purpose of this study was to compare the elements of treatment commonly associated with successful outcomes in the assessment of laminectomies - operating room times, estimated blood loss, length of stay, and complications - of the minimally invasive and open approach laminectomies. METHODS: We retrospectively reviewed the medical records and relevant imaging of 126 patients who underwent surgical decompression for lumbar stenosis. Thirty-eight patients underwent bilateral decompression via a unilateral minimally invasive technique, while 88 patients underwent bilateral decompression via a standard open technique. A chart review was performed to determine intraoperative blood loss, length of operative time, length of hospital stay, and number and nature of complications. RESULTS: The minimally invasive lumbar laminectomy (MID) patients had shorter operating room times, less estimated blood loss, shorter length of stay, and fewer complications. CONCLUSIONS: Bilateral decompression of lumbar spinal stenosis via a unilateral approach involves shorter operating times and less blood loss, less muscle dissection, fewer and less severe complications, and better mobility in the immediate postoperative period than open decompressive techniques. In addition, this technique is very similar to the commonly performed microendoscopic discectomy and is easily mastered over time.

Comparative evaluation of oral and intranasal priming with replication-competent adenovirus 5 host range mutant (Ad5hr)-simian immunodeficiency virus (SIV) recombinant vaccines on immunogenicity and protective efficacy against SIV(mac251).

Oral, replication-competent Ad-HIV vaccines are advancing to human trials. Previous evaluation of protective efficacy in non-human primates has primarily followed upper respiratory tract administrations. Here we compared sequential oral (O/O) versus intranasal/oral (I/O) priming of rhesus macaques with Ad5 host range mutant-SIV recombinants expressing SIV env/rev, gag, and nef genes followed by boosting with SIV gp120 protein. Cellular immune responses in PBMC were stronger and more frequent after I/O administration. Both groups developed mucosal immunity, including memory cells in bronchial alveolar lavage, and gut-homing receptors on PBMC. Following intrarectal SIV(mac251) challenge, both groups exhibited equivalent, significant protection and robust post-challenge cellular immunity. Our results illustrate the promise of oral replication-competent Ad-recombinant vaccines. Pre-challenge PBMC ELISPOT and proliferative responses did not predict protection in the O/O group, highlighting the need for simple, non-invasive methods to reliably assess mucosal immunity.

The response of serum apolipoprotein H to an oral fat load.

BACKGROUND: We tested the hypothesis that serum apolipoprotein H (apo H) concentration increases after an oral fat load. Such a study would give valuable insight into whether apo H was influenced by the postprandial state. METHODS: Ten male subjects aged 24-48 years were fed 62.5 g of total fat (saturates 12 g, monounsaturates 35.3 g, polyunsaturates 12.5 g). Venous blood was sampled hourly for 5 h post-oral fat load. RESULTS: No significant change in serum apo H concentration occurred following the oral fat load. However, serum apo H in the baseline samples correlated significantly with subject body mass index (r = 0.683, P < 0.05), body fat mass (r = 0.778, P < 0.01), lean body mass (r = 0.693, P < 0.05), serum triglyceride (r = 0.732, P < 0.02), serum insulin (r = 0.808, P < 0.01) and insulin resistance index (r = 0.794, P < 0.01). In stepwise multiple linear regression model, with serum apo A1, apo B, lipoprotein(a), total cholesterol, triglyceride, HDL-cholesterol, LDL-cholesterol, plasma glucose and insulin and apo H as the dependent variable, insulin remained in the model (r = 0.81, P < 0.01). Conversely, with body mass index, body fat mass, lean body mass and waist/hip ratio in the model and apo H as dependent variable, only body fat mass remained in the model (r = 0.78, P < 0.01). CONCLUSIONS: Serum apo H may be involved in insulin resistance and relates to various indices of adipose tissue, including body fat mass. However, serum apo H concentrations do not significantly change postprandially.

Substituting dietary saturated fat with polyunsaturated fat changes abdominal fat distribution and improves insulin sensitivity.

AIMS/HYPOTHESIS: British dietary recommendations are to decrease total fat intake to less than 30 % of daily energy intake and saturated fat to less than 10 %. In practice, it is difficult for people to make these changes. It may be easier to encourage people to switch from a diet rich in saturated fatty acids to one rich in polyunsaturated fatty acids. METHODS: A total of 17 subjects - six people with Type II (non-insulin-dependent) diabetes mellitus, six non-obese and five obese people without diabetes - were randomised to spend two 5-week periods on a diet rich in saturated or in polyunsaturated fatty acids, in a crossover design. At the start of the study and after each dietary period, we assessed abdominal fat distribution using magnetic resonance imaging, insulin sensitivity using hyperinsulinaemic-euglycaemic clamps and fasting lipid parameters. RESULTS: Dietary compliance, assessed by weekly 3-day dietary records and measurement of biochemical markers, was good. Energy and fat intake appeared to be reduced on the diet rich in polyunsaturated fatty acids although body weights did not change. Insulin sensitivity and plasma low density lipoprotein cholesterol concentrations improved with the diet rich in polyunsaturated fatty acids compared with the diet rich in saturated fatty acids. There was also a decrease in abdominal subcutaneous fat area. CONCLUSION/INTERPRETATION: If this result is confirmed in longer-term studies, this dietary manipulation would be more readily achieved by the general population than the current recommendations and could result in considerable improvement in insulin sensitivity, reducing the risk of developing Type II diabetes.

The response of serum sialic acid and other acute phase reactants to an oral fat load in healthy humans.

BACKGROUND: Elevated serum total sialic acid (TSA) has been shown to be associated with increased cardiovascular mortality. It has been postulated that atherogenesis is a postprandial phenomenon. We tested the hypothesis that serum TSA and other acute phase proteins, namely C-reactive protein (CRP) and fibrinogen, may be related to the postprandial state. METHODS: Ten healthy male subjects, aged 24-48 years, were fed 62.5 g of total fat (saturates 12 g, monounsaturates 35.3 g and polyunsaturates 12.5 g) in the form of strawberry flavoured Calogen. Venous blood was sampled hourly for 5 h. Concentrations of serum triglyceride, TSA and acute phase proteins were measured. RESULTS: Serum triglyceride concentration increased postprandially, peaking at 240 min. Serum CRP and plasma fibrinogen did not significantly increase after the oral fat load. However, serum TSA did increase from baseline (0.599+/-0.051 g/l) in response to the oral fat load, peaking at 120 min post-oral fat load (0.633+/-0.066 g/l, P<0.02). There was a significant correlation between serum TSA and plasma fibrinogen at baseline (rho=0.62, P=0.05) but not for serum CRP (rho=-0.22) or triglyceride (rho=0.21). CONCLUSIONS: We conclude that serum TSA increases postprandially and this finding gives further insight as to why the former is considered to be a cardiovascular risk factor.

Cognitive and other adverse effects of diphenhydramine use in hospitalized older patients.

BACKGROUND: Diphenhydramine hydrochloride is a commonly prescribed medicine in hospitalized patients, but its adverse effects on older patients remain unclear. METHODS: We enrolled 426 hospitalized medical patients aged 70 years or older in a prospective cohort study in a university hospital. Measurements included baseline and daily assessments including Mini-Mental State Examination scores, Confusion Assessment Method ratings, direct observations for medical devices (urinary catheter or physical restraints), and blinded medical record extractions for diphenhydramine use. RESULTS: Of the 426 patients, 114 (27%) received diphenhydramine during hospitalization and shared similar baseline characteristics including age, sex, delirium risk, and Mini-Mental State Examination scores compared with nonexposed patients. The diphenhydramine-exposed group was at an increased risk for any delirium symptoms (relative risk [RR], 1.7; 95% confidence interval [CI], 1.3-2.3) and for individual delirium symptoms, including inattention (RR, 3.0; 95% CI, 1.5-5.9), disorganized speech (RR, 5.5; 95% CI, 1.0-29.8), and altered consciousness (RR, 3.1; 95% CI, 1.6-6.1). Exposed patients also had increased risk for urinary catheter placement (RR, 2.5; 95% CI, 1.0-6.0) and longer median length of stay (7 vs 6 days; P =.009). A dose-response relationship was demonstrated for most adverse outcomes. Overall, 24% of diphenhydramine doses were administered inappropriately. CONCLUSIONS: Diphenhydramine administration in older hospitalized patients is associated with an increased risk of cognitive decline and other adverse effects with a dose-response relationship. Careful review of its use is necessary in this vulnerable population.

The effect on adipose tissue blood flow of isoenergetic meals containing different amounts and types of fat.

OBJECTIVE: To investigate the factors regulating the increase in adipose tissue blood flow following meals. DESIGN: Eight subjects were fed three isoenergetic meals; two high-fat meals rich in either saturated or polyunsaturated fatty acids and one low-fat, high-carbohydrate meal. MEASUREMENTS: Blood samples were taken and adipose tissue blood flow was measured before and for 6 h after the meal. Plasma glucose, insulin, non-esterified fatty acid, total and chylomicron-triacylglycerol and catecholamine concentrations were measured. RESULTS: Adipose tissue blood flow rose to a peak after all three meals (P<0.05 for each). The three meals stimulated adipose tissue blood flow at similar times. There was a marked and statistically significant similarity in the time course of changes in blood flow and insulin concentrations. In contrast, noradrenaline concentrations peaked later than adipose tissue blood flow (P=0.014). CONCLUSION: Adipose tissue blood flow may be 'carbohydrate-stimulated' rather than 'fat-stimulated', with insulin having a vasodilatory role in adipose tissue as in skeletal muscle.